Pharmacokinetics of cefonicid in lactating goats after intravenous, intramuscular and subcutaneous administration, and after a long-acting formulation for subcutaneous administration.

The single-dose disposition kinetics of cefonicid were determined in clinically normal lactating goats (n = 6) after intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration of a conventional formulation, and after subcutaneous administration of a long-acting formulation (SC-LA). Cefonicid concentrations were determined by high performance liquid chromatography with ultraviolet detection. The concentration-time data were analysed by noncompartmental pharmacokinetic methods. Steady-state volume of distribution (Vss ) and clearance (Cl) of cefonicid after IV administration were 0.14 ± 0.03 L/kg and 0.51 ± 0.07 L/h·kg, respectively. Following IM, SC and SC-LA administration, cefonicid achieved maximum plasma concentrations of 14.46 ± 0.82, 11.98 ± 1.92 and 17.17 ± 2.45 mg/L at 0.26 ± 0.13, 0.42 ± 0.13 and 0.83 ± 0.20 hr, respectively. The absolute bioavailabilities after IM, SC and SC-LA routes were 75.34 ± 11.28%, 71.03 ± 19.14% and 102.84 ± 15.155%, respectively. After cefonicid analysis from milk samples, no concentrations were found above LOQ at any sampling time. From these data, cefonicid administered at 20 mg/kg each 12 hr after SC-LA could be effective to treat bacterial infections in lactating animals not affected by mastitis problems.

Influence of the ischaemic tourniquet in antibiotic prophylaxis in total knee replacement.

OBJECTIVE: There is level iv evidence that the preoperative administration of antibiotics helps in the prevention of prosthetic infection. There is controversy on whether the ischemia applied during surgery may affect the minimum inhibitory concentration of the antibiotic in the peri-prosthetic tissues. The aim of this study is to review this phenomenon through the determination of antibiotic concentration in the synovial tissue. MATERIAL AND METHOD: A prospective observational clinical study was conducted on 32 patients undergoing total knee replacement. Cefonicid 2g was administered as prophylaxis, with a tourniquet used for all patients. The antibiotic concentration was quantified by high performance liquid chromatography in samples of synovial tissue collected at the beginning and at the end of the intervention. RESULTS: The mean concentration of antibiotic was 23.16 µg/g (95% CI 19.19 to 27.13) in the samples at the beginning of the intervention and 15.45 µg/g (95% CI 13.20 to 17.69) in the final samples, being higher than the minimum inhibitory concentration of cefonicid, set at 8 µg/g. These results were statistically significant for both concentrations (P<.00001). DISCUSSION: The antibiotic concentration throughout the standard total knee prosthesis surgery performed with tourniquet gradually decreases throughout the intervention. The concentration determined at the end of the intervention was higher than the minimum inhibitory concentration required for the antibiotic studied. In conclusion, the use of a tourniquet does not increase the risk of infection.

Acute bacterial peritonitis: permeability of cephalosporins in the peritoneal cavity.

Acute bacterial peritonitis is a common surgical disease treated with fluid resuscitation, surgery and antibiotics. The choice and use of antibiotics is an important supplement of therapy. Cephalosporins are among the most frequently used drugs for this condition. Although there is evidence that these agents reach the peritoneal cavity under normal conditions, no data are available regarding their delivery and concentration during acute secondary bacterial peritonitis. In order to determine the effectiveness of these agents in such cases, we studied the diffusion of three generations of cephalosporins--cefazolin, cefonicid and cefotaxime--into the peritoneal cavity during controlled bacterial peritonitis in rats. Our results show that all three drugs reached therapeutic concentrations in the peritoneal fluid; the highest concentration was obtained by the third-generation cefotaxime.

[Excretion of cefonicid and ceftriaxone into the saliva]. / Cefonicid és ceftriaxon nyálba történö kiválasztódásának vizsgálata.

The serum and saliva levels of cefonicid (Monocid) and ceftriaxon (Rocephin) were studied after iv. administration on mice. It was found that both of the antibiotics were secreted well into saliva and their therapeutic values remained for 4-5 hours.

Randomized trial comparing ceftriaxone with cefonicid for treatment of spontaneous bacterial peritonitis in cirrhotic patients.

We compared cefonicid (2 g every 12 h) and ceftriaxone (2 g every 24 h) for their efficacy and safety in treating spontaneous bacterial peritonitis in cirrhotic patients in an open randomized clinical trial (30 patients in each group). Clinical, laboratory, and bacteriologic characteristics were similar in both groups. Ceftriaxone-susceptible strains were isolated on 44 occasions (94%), and cefonicid-susceptible strains were isolated on 43 occasions (91.5%). The antibiotic concentration in ascitic fluid/MIC ratio for ceftriaxone was > 100 throughout the dose interval (24 h), while it was lower for cefonicid (between 1 and 18). A total of 100% of patients treated with ceftriaxone, and 94% of those treated with cefonicid were cured of their infections (P was not significant). Hospitalization mortality was 37% in the cefonicid group and 30% in the ceftriaxone group (P was not significant). The time that elapsed between the initiation of treatment and the patient's death was shorter in the cefonicid group patients (5.3 +/- 3.90 days) than in the ceftriaxone group patients (11.8 +/- 9.15 days) (P < 0.05). None of the patients presented with superinfections, and only two patients treated with cefonicid and three patients treated with ceftriaxone developed colonizations with Enterococcus faecalis or Candida albicans. Ceftriaxone and cefonicid are safe and useful agents for treating cirrhotic spontaneous bacterial peritonitis, although the pharmacokinetic characteristics of ceftriaxone seem to be more advantageous than those of cefonicid.

Disposition of intramuscular cefonicid in elderly patients.

OBJECTIVE: To examine the disposition of intramuscular (IM) cefonicid in elderly patients with bacterial pneumonia. DESIGN: Pharmacokinetic study. SETTING: A 620-bed university-affiliated long-term care institution with its own 39-bed acute care unit. PATIENTS: Nine consecutive elderly patients with bacterial pneumonia treated with IM cefonicid. MEASUREMENTS: Blood samples were collected on the seventh day of therapy over a 24-hour period and analyzed by high performance liquid chromatography. Pharmacokinetics parameters (volume of distribution, half-life, and clearance) and protein binding were calculated. Clinical outcome of IM cefonicid therapy was also noted. RESULTS: The estimated creatinine clearance (CIcr) ranged from 32 to 145 mL/min. Peak cefonicid serum concentrations occurred at 0.5-1.5 hours, with a mean value of 118 +/- 41 micrograms/mL. Cefonicid concentrations declined monoexponentially to 57 +/- 16 micrograms/mL at 12 hours and 28 +/- 14 micrograms/mL at 24 hours. The mean apparent distribution volume was 0.2 +/- 0.07 L/kg, and the mean apparent total clearance was 15 +/- 12 mL/min. The half-life ranged from 3.1 to 38 hours. A linear correlation was noted between Clcr and cefonicid clearance (r = 0.99). CONCLUSIONS: Cefonicid absorption was variable among these patients, and the serum half-life was longer than previous values noted in younger patients with similar degree of renal dysfunction. Pharmacokinetic and clinical outcome data from our study group indicate the potential role of IM cefonicid in treating elderly patients with bacterial pneumonia.

Influence of angiotensin II-induced alterations in renal flow on excretion of cefonicid in isolated perfused rat kidneys.

The effects of variations in renal perfusate flow on the excretion of cefonicid was examined in isolated perfused rat kidneys. Cefonicid, an expanded-spectrum cephalosporin, is primarily eliminated by active tubular secretion and is neither metabolized nor reabsorbed in the isolated kidney. We used angiotensin II (AII), a strong vasoconstrictor hormone of the afferent and the efferent arterioles in the kidney, to determine whether the renal and secretion clearances, as well as the excretion ratio (ER = CLR/[fu x GFR], where CLR is renal clearance, fu is the unbound fraction, and GFR is glomerular filtration rate), of this low-extraction compound can be altered by a decreased perfusion flow. Control studies were performed in the absence (n = 5) and presence (n = 4) of AII; cefonicid studies were performed in the absence (n = 4) and presence (n = 5) of AII. AII (1 to 4 ng/min) and cefonicid (5 to 10 micrograms/min) were infused into the perfusate. Cefonicid was assayed by high-performance liquid chromatography, and its protein binding was determined by ultrafiltration. AII decreased the perfusate flow rate and increased the renal vascular resistance and filtration fraction of the isolated kidney in the presence and absence of cefonicid. The glomerular filtration rate remained unchanged among the groups. The fractional excretion of glucose was low and steady, indicating a well-preserved tubular function. Although the unbound fraction was unchanged between treatments, the renal and secretion clearances and the excretion ratio of cefonicid were reduced by about 40% in the presence of AII (excretion ratios, 10.3 without AII versus 6.03 with AII). These results suggest that the altered clearance parameters of cefonicid are the result of a flow-induced change in the intrinsic secretory transport of the drug.

Influence of the unbound concentration of cefonicid on its renal elimination in isolated perfused rat kidneys.

The effect of variations in plasma protein binding on the renal excretion of cefonicid was assessed by using isolated perfused rat kidneys. Cefonicid exhibits preferential binding ex vivo to human serum albumin (HSA), as opposed to bovine serum albumin (BSA), and is eliminated mainly by tubular secretion, a process that was reported to be dependent on the total drug concentration. This contradicts previous studies with antimicrobial compounds and other drugs of low renal extraction in which the unbound drug concentration was shown to be the driving force for carrier-mediated tubular transport. To clarify this discrepancy, we performed perfusion studies by using 6% BSA at initial concentrations of 200 micrograms/ml (n = 6) and 20 micrograms/ml (n = 9) and in a combination of 4% BSA plus 2% HSA at initial concentrations of 200 micrograms/ml (n = 4). The excretion ratio [ER = CLR/(fu x GFR)] of cefonicid decreased with increasing unbound concentrations, whereas no apparent relationship with the total concentration was evident. At similar total concentrations of cefonicid, the renal clearance remained unchanged; the secretion clearance increased significantly in the 4% BSA-2% HSA experiments, reflecting the reduced unbound fraction and unbound drug concentration of cefonicid. The excretion ratio data were compatible with a model in which Michaelis-Menten kinetics were required to describe active transport and secretion was dependent on the unbound cefonicid concentration. As a result, changes in plasma protein binding as a result of drug interactions or disease states could significantly influence the tubular transport capability of compounds with low renal extraction.

Cefonicid versus clindamycin prophylaxis for head and neck surgery in a randomized, double-blind trial, with pharmacokinetic implications.

Perioperative single-dose antibiotic prophylaxis of cefonicid was compared with clindamycin in a prospective, randomized, double-blind trial of patients undergoing oncologic head and neck surgery. Antibiotics were administered intravenously beginning 1 to 2 h preoperatively. Cefonicid, 1 g, was given as a single dose. Clindamycin, 600 mg, was administered every 8 h for a total of four doses. Blood and wound drainage samples were collected for 24 h following the dose of cefonicid and assayed for total and free cefonicid concentrations, using reverse-phase high-performance liquid chromatography. Although total concentrations of cefonicid in both serum and wound drainage exceeded the MIC for 90% of the isolates of common bacterial pathogens for 24 h, free concentrations in serum and wound drainage (11.0 and 14.9% of total concentrations) were subinhibitory within 6 h following administration. Free concentrations of cefonicid in the postoperative wound drainage were subinhibitory for the entire study period, both perioperatively and postoperatively. Postoperative wound infection occurred significantly (P less than 0.05) more frequently in patients receiving cefonicid (24%) as compared with those receiving clindamycin (8.2%). The relatively low free levels of cefonicid achieved in serum and wound drainage were attributed to the high degree of protein binding (89% in serum) and may be related to the poor clinical outcome.

Penetration of cefonicid into serum, salpinges, cervix and vaginal tissue.

Cefonicid is a new cephalosporin that, given in adequate concentrations is able to kill some pathogens such as Gram-positive cocci and many Enterobacteriaceae. In this study we have evaluated 40 patients receiving 1 g of cefonicid i.m. at various times before abdominal or vaginal hysterectomy. The results of the present study indicate that a single dose of 1 g of cefonicid given intramuscularly is useful as prophylaxis and treatment of gynecological infections.

Penetration of cefonicid into human lung tissue and lymph nodes.

The present study was undertaken in order to investigate the penetration of cefonicid, a long-acting parenteral cephalosporin, with enhanced activity against most gram-positive and gram-negative pathogens, into human lung tissue and lymph nodes in patients undergoing open thoracotomy. Samples of lung tissue, lymph nodes and serum were obtained at various times after a single intramuscular dose of 1 g. The concentration of cefonicid was assayed by an agar diffusion method with Bacillus subtilis used as the test organism. The mean concentrations of cefonicid in serum at 2, 4, 8, 12 and 24 h after the injection were 91.5, 66.1, 35.7, 21.8 and 2.9 micrograms/ml, respectively. The mean levels of cefonicid into the hilar lymph nodes at the same times were 22.3, 18.7, 12.0, 6.9 and 1.5 micrograms/ml, respectively, while its concentrations in lung tissue were lower than those in lung lymph nodes up to the 12th hour (12.1, 14.6, 7.8, 5.4 and 1.9 micrograms/ml, respectively). Our results show that cefonicid was well distributed in interstitial fluid from which pulmonary lymph is formed and that its concentrations in lung tissue and lymph nodes were sufficient to inhibit most pathogens involved in respiratory tract infections. This finding was considered important, because it demonstrated that the high binding by plasma protein of cefonicid did not prevent it from entering lung tissue and fluids in useful quantities.

Cefonicid distribution into tonsillar tissue.

The kinetic profile in tonsils of cefonicid has been studied in 30 patients who underwent tonsillectomy after administration of a single intramuscular dose of 1 g. Blood and tissue samples were withdrawn 1, 2, 3, 6, 12 and 24 h after administration of the drug. The analytical determination was performed employing a microbiological method. Peak serum levels appeared at the first hour (94.2 +/- 9.83 mg/l), while peak tissue values were determined in samples collected at the third hour (11.9 +/- 3.68 mg/kg). Serum levels at the 24th hour were 3.82 +/- 1.25 mg/l. Levels in the tonsils were 7.54 +/- 2.96 mg/kg at the sixth hour, 3.34 +/- 1.42 mg/kg at the twelfth hour and 0.40 +/- 0.31 mg/kg at the 24th hour.

[Pulmonary and tonsillar distribution of ceftriaxone and cefonicid and the resultant bactericidal activity of the organ]. / Distribuzione polmonare e tonsillare di ceftriaxone e cefonicid e risultante attività battericida d'organo.

The therapeutic efficacy of Ceftriaxone and Cefonicid 1 g I.M. single-dose against S. Pneumoniae, H. Influenzae and K. Pneumoniae in tonsil and lung infections was studied using bactericidal quotient (BQ). Samples of lung tissue and serum were obtained from two groups of surgical patients, treated with Ceftriaxone or Cefonicid 1 g I.M., 2-8-16 and 24 hours before surgery. From two other groups of 10 surgical patients, treated as above, samples of tonsil tissue and serum were obtained. In lung tissue the higher levels of Ceftriaxone and Cefonicid appeared at the second hour (11.54 +/- 1.59 mcg/g and 11.4 +/- 2.49 mcg/g respectively); the lower values were observed at the 24th hour (2.18 +/- 0.47 mcg/g for Ceftriaxone and 0.64 +/- 0.21 mcg/g for Cefonicid). Higher Ceftriaxone and Cefonicid levels also appeared in tonsil tissue at the 2nd hour (11.12 +/- 2.42 mcg/g and 9.22 +/- 3.12 mcg/g respectively); the lower values were observed at the 24th hour (1.54 +/- 0.46 mcg/g for Ceftriaxone and 0.42 +/- 0.23 mcg/g for Cefonicid). BQ values were estimated using the ratio between the mean concentrations of Ceftriaxone and Cefonicid in tissue samples and the MBC mean values determined for the above mentioned pathogens, isolated in hospital. Ceftriaxone always showed BQ values greater than 1 during 24 hours versus levels observed for the three reported pathogens. Cefonicid showed BQ values greater than 1 during 24 hours against S. Pneumoniae and BQ values less than 1 for 6-8 hours against H. Influenzae and for 1-4 hours against K. Pneumoniae.

Cortical and medullary kidney tissue levels of cefonicid in human beings.

Cefonicid concentration has been determined microbiologically in cortical and medullary tissue in 30 patient undergoing surgery because of neoplastic disease localized within the kidney. Each subject received 1 g of cefonicid intramuscularly in a single administration. The patients were divided into six groups, from which samples of blood and tissue were collected 2, 4, 6, 8, 12, 24 h respectively after treatment with the drug. The mean peak serum levels appeared at the second hour (74.96 +/- 8.14 mcg/ml) and the decay shows a monoexponential behaviour, reaching a minimum value of 5.4 +/- 2.33 mcg/ml at the 24th hour. In the cortical tissue of the kidney the peak levels appeared at the fourth hour (26.22 +/- 8.87 mcg/g), while at the 24th hour levels were about 3.08 +/- 0.81 mcg/g. A very similar behaviour could also be observed in the medullary tissue of the kidney with peak levels at the fourth hour (25.82 +/- 10.06 mcg/g) and levels of 3.48 +/- 0.85 mcg/g at the 24th hour. A delay in the decay of tissue levels in comparison with the decay of blood levels could be observed from the eighth hour.